Convergent processes for preparing macrolide antibacterial agents

ABSTRACT

The invention described herein relates to processes for preparing ketolide antibacterial agents. In particular, the invention relates to intermediates and processes for preparing ketolides that include a 1,2,3-triazole substituted side chain.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims, under 35 U.S.C. § 119(e), the benefit ofand priority to U.S. Provisional Application No. 61/786,914 filed Mar.15, 2013, which is hereby incorporated herein by reference.

TECHNICAL FIELD

The invention described herein relates to processes for preparingketolide antibacterial agents. In particular, the invention relates tointermediates and processes for preparing ketolides that include a1,2,3-triazole substituted side chain.

BACKGROUND AND SUMMARY

The use of macrolides for various infectious diseases is well known.Erythromycin was the first compound of this class to be introduced intoclinical practice. Since then, additional macrolides, includingketolides have garnered much attention for their ability to treat a widerange of disease states. In particular, macrolides are an importantcomponent of therapies for treating bacterial, protozoal, and viralinfections. In addition, macrolides are often used in patients allergicto penicillins.

Illustrative of their wide ranging uses, macrolide compounds have beenfound to be effective for the treatment and prevention of infectionscaused by a broad spectrum of bacterial and protozoal pathogens. Theyare also useful for treating respiratory tract infections and softtissue infections. Macrolide antibiotics are found to be effective onbeta-hemolytic streptococci, pneumococci, staphylococci, andenterococci. They are also found to be effective against mycoplasma,mycobacteria, some rickettsia, and chlamydia.

Macrolide compounds are characterized by the presence of a large lactonering, which is generally a 14, 15, or 16-membered macrocyclic lactone,to which one or more saccharides, including deoxy sugars such ascladinose and desosamine, may be attached. For example, erythromycin isa 14-membered macrolide that includes two sugar moieties. Spiramycinbelongs to a second generation of macrolide compounds that include a16-membered ring. Third generation macrolide compounds include forexample semi-synthetic derivatives of erythromycin A, such asazithromycin and clarithromycin. Finally, ketolides represent a newerclass of macrolide antibiotics that have received much attentionrecently due to their acid stability, and most importantly due to theirexcellent activity against organisms that are resistant to othermacrolides. Like erythromycins, ketolides are 14-membered ring macrolidederivatives characterized by a keto group at the C-3 position (Curr.Med. Chem., “Anti-Infective Agents,” 1:15-34 (2002)). Ketolide compoundsare also currently under clinical investigation.

Liang et al. in U.S. Patent Appl. Pub. No. 2006/0100164, the disclosureof which is incorporated herein by reference, describes a new series oftriazole-containing ketolide compounds, and an illustrative synthesisthereof. These new compounds show excellent activity against pathogenicorganisms, including those that have already exhibited resistance tocurrent therapies. However, it has been discovered herein thatside-reactions occur in the processes disclosed by Liang et al leadingto impurities that are difficult to remove, and low yields. In addition,starting material impurities are also difficult to remove. Thoseside-reactions decrease the overall yield of the desired compounds, andthose side-products and impurities may complicate the purification ofthe desired compounds. The occurrence of such side reactions and thepresence of such impurities are exacerbated on large commercial scales.In addition, the processes disclosed by Liang et al. include an azideintermediate, which at larger commercial manufacturing scales, may beundesirable, or represent a safety issue. Due to the importance of thesetriazole-containing ketolide compounds for use in providing beneficialtherapies for the treatment of pathogenic organisms, alternative and/orimproved processes for their preparation are needed.

The azide intermediate may be avoided by a process that incorporates theside chain intact. However, it has also been reported that introductionof an intact side chain is not a viable process (see, Lee et al.,“Process Development of a Novel Azetidinyl Ketolide Antibiotic” Org.Process Res Dev 16:788-797 (2012)). In particular, it has been reportedthat introduction of an intact side chain leads to an isomeric mixtureof products. In addition, it has been reported that introduction of theintact side chain provides only a low yield (<20%).

It has been unexpectedly discovered herein that triazole-containing sidechains do not result in an isomeric mixture of products. It has alsobeen unexpectedly discovered herein that triazole-containing side chainsprovide high yielding reactions. It has also been unexpectedlydiscovered herein that if the side chain is introduced before theremoval of the cladinose, then a single isomer is obtained. It has alsobeen unexpectedly discovered herein that if the side chain is introducedbefore the removal of the cladinose, then the process provides a highyield.

Described herein are new processes that may be advantageous in preparingcompounds of formula (I) that avoid such side-products, and/or may bepurified to higher levels of purity. In addition, the processesdescribed herein avoid the azide intermediate by proceeding through aconvergent synthetic route.

In one illustrative embodiment of the invention, processes andintermediates are described for preparing compounds of formula (I):

and pharmaceutically acceptable salts, solvates, and hydrates thereof;wherein

R¹ is a desosamine or a desosamine derivative;

A is —CH₂—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)₂—, —S(O)₂NH—,—C(O)NHS(O)₂—;

B is —(CH₂)_(n)— where n is an integer ranging from 0-10; or B issaturated C₂-C₁₀; or B is unsaturated C₂-C₁₀, which may contain one ormore alkenyl or alkynyl groups; or -A-B-taken together is alkylene,cycloalkylene, or arylene;

C represents 1 or 2 substituents independently selected in each instancefrom hydrogen, halogen, hydroxy, acyl, acyloxy, sulfonyl, ureyl, andcarbamoyl, and alkyl, alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl,and heteroarylalkyl, each of which is optionally substituted; and

W is hydrogen, F, Cl, Br, I, or OH.

In another illustrative embodiment, processes and intermediates aredescribed herein for preparing11-N-[[4-(3-aminophenyl)-1,2,3-triazol-1-yl]-butyl]-5-desosaminyl-2-fluoro-3-oxoerythronolideA, 11,12-cyclic carbamate, also known as OP-1068, CEM-101, andsolithromycin.

In another embodiment of the compounds of formula (I), R¹ is adesosamine that includes an optionally protected 2′-hydroxy group. Inanother embodiment, R¹ is a desosamine that includes a protected2′-hydroxy group. In another embodiment, the protecting group is an acylgroup. In another embodiment, the protecting group is a stericallyhindered acyl group, such as a branched alkyl, aryl, heteroaryl,arylalkyl, arylalkyl, or heteroarylalkyl acyl group, each of which isoptionally substituted. In another embodiment, the protecting group isan optionally substituted benzoyl group. In another embodiment, theprotecting group is a benzoyl group. In another embodiment, -A-B— isalkylene, cycloalkylene, or arylene. In another embodiment, -A-B— isalkylene. In another embodiment, -A-B— is C₃-C₅ alkylene. In anotherembodiment, -A-B— is C₄ alkylene. In another embodiment, -A-B— is—(CH₂)₄—. In another embodiment, C is optionally substituted aryl,heteroaryl, arylalkyl, or heteroarylalkyl. In another embodiment, C isoptionally substituted aryl or heteroarylalkyl. In another embodiment, Cis optionally substituted aryl. In another embodiment, C is substitutedaryl. In another embodiment, C is amino substituted aryl. In anotherembodiment, C is amino substituted phenyl. In another embodiment, C is3-aminophenyl. In another embodiment, W is H or F. In anotherembodiment, W is F.

It is to be understood that each and every combination, and each andevery selection, and combination thereof, of the forgoing and followingembodiments is described herein. For example, in another embodiment, R¹is a desosamine that includes a protected 2′-hydroxy group, where theprotecting group is an acyl group; or R¹ is a desosamine that includes aprotected 2′-hydroxy group, where the protecting group is a stericallyhindered acyl group; or R¹ is a desosamine that includes a protected2′-hydroxy group, where the protecting group is a benzoyl group, and-A-B— is C₃-C₅ alkylene; or R¹ is a desosamine that includes a protected2′-hydroxy group, where the protecting group is a benzoyl group, and-A-B— is —(CH₂)₄—; or R¹ is a desosamine that includes a protected2′-hydroxy group, where the protecting group is a benzoyl group, and-A-B— is —(CH₂)₄—, and C is optionally substituted aryl; or R¹ is adesosamine that includes a protected 2′-hydroxy group, where theprotecting group is a benzoyl group, and -A-B— is —(CH₂)₄—, and C is3-aminophenyl; and so forth.

It is to be understood that the processes described herein may beadvantageously performed simply and cost-effectively. It is further tobe understood that the processes described herein may be scaled to largeproduction batches. It is further to be understood that the processesdescribed herein are performed in fewer steps than conventionalprocesses. It is further to be understood that the processes describedherein are performed are more convergent, and/or require shorter linearsub-processes, than conventional processes. It is further to beunderstood that the processes described herein may concomitantly producefewer or different side products than known processes. It is further tobe understood that the processes described herein may yield compoundsdescribed herein in higher purity than known processes.

DETAILED DESCRIPTION

Several illustrative embodiments of the invention are described by thefollowing enumerated clauses:

1A. A process for preparing a compound of formula (I) as describedherein, the process comprising the step of

(A) contacting a compound of formula

or a salt thereof, where R¹⁰⁰ is a hydroxyl protecting group, and L is aleaving group, with a compound of formula

or a salt thereof, where C is as defined herein, and C^(P) is aprotected form of C, and a base, to prepare a compound of formula

or a salt thereof; or

(B) contacting a compound of formula

or a salt thereof, with one or more protecting group forming agents toprepare a compound of formula

or a salt thereof; or

(C) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(D) contacting a compound of formula

or a salt thereof, with one or more protecting group forming agents toprepare a compound of formula

or a salt thereof; or

(E) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound offormula

or a salt thereof; or

(F) contacting a compound of formula

or a salt thereof, with a hydroxylating or halogenating agent to preparea compound of formula

or a salt thereof; or

(G1) contacting a compound of formula

or a salt thereof, with a hydroxy deprotecting agent to prepare acompound of formula

or a salt thereof; or

(G2) contacting a compound of formula

or a salt thereof, with one or more deprotecting agents to prepare thecorresponding deprotected compound of formula

or a salt thereof; or any combination of the foregoing.

1B. The process of clause 1A wherein steps (G1) and (G2) are performedsequentially, contemporaneously, or simultaneously.

1C. The process of clause 1A wherein steps (G1) and (G2) are performedsimultaneously.

1D. The process of clauses 1 wherein the deprotecting agent and thehydroxy deprotecting agent are the same.

1E. The process of clauses 1 wherein C^(P) is N^(P)-substituted phenyl.

2A. A process for preparing a compound of formula (I) as describedherein, the process comprising the step of

(a) contacting a compound of formula

or a salt thereof, where R¹⁰⁰ is a hydroxyl protecting group, and L is aleaving group, with a compound of formula

or a salt thereof, where N^(P) is a protected amine, and a base; toprepare a compound of formula

or a salt thereof; or

(b) contacting a compound of formula

or a salt thereof, with an amine protecting group forming agent toprepare a compound of formula

or a salt thereof; or

(c) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(d) contacting a compound of formula

or a salt thereof, with an amine protecting group forming agent toprepare a compound of formula

or a salt thereof; or

(e) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound offormula

or a salt thereof; or

(f) contacting a compound of formula

or a salt thereof, with an amine deprotecting agent to prepare acompound of formula

or a salt thereof; or

(g) contacting a compound of formula

or a salt thereof, with a fluorinating agent to prepare a compound offormula

or a salt thereof; or

(h1) contacting a compound of formula

or a salt thereof, with a hydroxy deprotecting agent to prepare acompound of formula

or a salt thereof; or

(h2) contacting a compound of formula

or a salt thereof, with an amine deprotecting agent to prepare acompound of formula

or a salt thereof; or

any combination of the foregoing.

2B. The process of clause 2A wherein steps (h1) and (h2) are performedsequentially, contemporaneously, or simultaneously.

2C. The process of clause 2A wherein steps (h1) and (h2) are performedsimultaneously.

3. The process of clauses 2 wherein the amine protecting group formingagent is an acylating agent or amide, carbamate, or urea forming agent.

4. The process of any one of clauses 2 to 3 wherein the aminedeprotecting agent and the hydroxyl deprotecting agent are the same,such as ammonia or ammonium hydroxide and a solvent.

5. The process of any one of clauses 1 to 4 wherein N^(P) is NHC(O)CF₃.

6A. A process for preparing a compound of formula (I) as describedherein, the process comprising the step of

(a′) contacting a compound of formula

or a salt thereof, where R¹⁰⁰ is a hydroxyl protecting group, and L is aleaving group, with a compound of formula

or a salt thereof, and a base; to prepare a compound of formula

or a salt thereof; or

(b′) contacting a compound of formula

or a salt thereof, with an acid to prepare a compound of formula

or a salt thereof; or

(c′) contacting a compound of formula

or a salt thereof, with an oxidizing agent to prepare a compound offormula

or a salt thereof; or

(d′) contacting a compound of formula

or a salt thereof, with a fluorinating agent to prepare a compound offormula

or a salt thereof; or

(e′) contacting a compound of formula

or a salt thereof, with a hydroxy deprotecting agent to prepare acompound of formula

or a salt thereof; or

(f′) contacting a compound of formula

or a salt thereof, with a reducing agent to prepare a compound offormula

or a salt thereof; or

any combination of the foregoing.

6B. The process of clause 6A wherein steps (e′) and (f′) are performedsequentially, contemporaneously, or simultaneously.

6C. The process of clause 6A wherein steps (e′) and (f′) are performedsimultaneously.

7. The process of clauses 6 wherein the hydroxy deprotecting agent andthe reducing agent are the same.

8. The process of any one of clauses 1 to 7 wherein the leaving group ishalo, pentafluorophenoxy, a sulfonate, such as triflate, a hydroxyamino,such as an HOBt, or imidazol-1-yl.

9. The process of any one of clauses 1 to 8 wherein the leaving group isimidazol-1-yl.

10. The process of any one of clauses 1 to 9 wherein the base is DBU.

11A. The process of any one of clauses 1 to 10 wherein the acid isaqueous HCl, such as 5% HCl, optionally with an organic cosolvent, suchas a ketone, such as acetone.

11B. The process of any one of clauses 1 to 10 wherein the acid is HClin an organic cosolvent, such as a ketone, such as acetone, or analcohol, such as methanol, or a combination thereof.

12. The process of any one of clauses 1 to 11 wherein N^(P) is an amideor carbamate, such as Bz-NH, CF₃C(O)—NH, Cbz-NH, Boc-NY, Fmoc-NY,BsMoc-NH, Trityl-NH, MeOTrityl-NH, and the like

13. The process of any one of clauses 1 to 12 wherein the amineprotecting group forming agent is TFAA.

14. The process of any one of clauses 1 to 12 wherein the amineprotecting group forming agent is benzoyl chloride.

15. The process of any one of clauses 1 to 12 wherein the amineprotecting group forming agent is Boc-anhydride.

16. The process of any one of clauses 1 to 12 wherein the amineprotecting group forming agent is Fmoc chloride.

17. The process of any one of clauses 1 to 12 wherein the protectedamine is formed in the presence of base, such a TEA.

18. The process of any one of clauses 1 to 17 wherein the oxidizingagent is trifluoroacetic anhydride in pyridine, PCC, Jones oxidation,TEMPO/NaOCl, Swern oxidation, Dess-Martin reagent, or Corey-Kim reagent.

19. The process of any one of clauses 1 to 17 wherein the oxidizingagent is N-chlorosuccinimide (NCS)/DMS.

20. The process of any one of clauses 1 to 19 wherein the fluorinatingagent is NFSI, F-TEDA, or Selectfluor.

21. The process of any one of clauses 1 to 20 wherein the aminedeprotecting agent is an amide hydrolyzing, cleaving, or removing agent.

22. The process of any one of clauses 1 to 20 wherein the aminedeprotecting agent is hydrogen, such as hydrogen gas or hydrogenproduced in situ, such as by transfer hydrogenation, such as by atransfer hydrogenation agent like formic acid, ammonium formate, and thelike, and a metal catalyst.

23. The process of any one of clauses 1 to 20 wherein the aminedeprotecting agent is ammonia, aqueous ammonia, or ammonia or aqueousammonia with an organic cosolvent, such as an alcohol, such as methanol.

24. The process of any one of clauses 1 to 20 wherein the aminedeprotecting agent is a carbamate hydrolyzing, cleaving, or removingagent.

25. The process of any one of clauses 1 to 24 wherein the deprotectingagent is an acid, such as TFA.

26. The process of any one of clauses 1 to 25 wherein the hydroxydeprotecting agent is an ester hydrolyzing, cleaving, or removing agent.

27. The process of any one of clauses 1 to 25 wherein the hydroxydeprotecting agent is an alcohol, such as methanol.

28. The process of any one of clauses 1 to 27 wherein the reducing agentis hydrogen, such as hydrogen gas or hydrogen produced in situ, such asby transfer hydrogenation, such as by a transfer hydrogenation agentlike formic acid, ammonium formate, and the like, and a metal catalyst.

29. The process of clause 28 wherein the metal catalyst is 5% Pd—C, 5%Pt—C, 10% Pd—C, 10% Pd—C, Pearlman's Catalyst, 20% Pd(OH)2, Raney-Ni,nickel sponge, iron, and the like.

30. The process of any one of clauses 1 to 29 wherein C is aryl,heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionallysubstituted.

31. The process of any one of clauses 1 to 30 wherein A is CH₂.

32. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n).

33. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is an integer between 2 and 6.

34. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is an integer between 2 and 5.

35. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is an integer between 3 and 6.

36. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is an integer between 3 and 5.

37. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is an integer between 3 and 4.

38. The process of any one of clauses 1 to 31 wherein B is (CH₂)_(n),and n is 3.

39. The process of any one of clauses 1 to 38 wherein R¹⁰⁰ is acyl.

40. The process of any one of clauses 1 to 38 wherein R¹⁰⁰ isalkylcarbonyl or optionally substituted benzoyl.

41. The process of any one of clauses 1 to 38 wherein R¹⁰⁰ is acetyl orbenzoyl, or R¹⁰⁰ is benzoyl.

42. The process of any one of clauses 1 to 41 wherein W is H or F.

43. The process of any one of clauses 1 to 41 wherein W is F.

In another illustrative embodiment, R¹⁰⁰ is a hydroxy protecting group,such as an acyl group. Additional hydroxyl protecting groups aredescribed in Greene & Wuts, “Protective Groups in Organic Synthesis,”2nd Ed. John Wiley & Sons, Inc., the disclosure of which is incorporatedherein by reference. In another embodiment, R100 is such an additionalhydroxyl protecting. In another illustrative embodiment, R¹⁰⁰ is asterically hindered acyl group; formed with a sterically hinderedacylating agent R¹⁰⁰-L, wherein R¹⁰⁰ is a sterically hindered acyl groupand L is a leaving or activating group, to form the corresponding2′-acyl derivative.

Illustrative sterically hindered acyl or diacyl derivatives include butare not limited to cyclohexylcarbonyl, benzoyl, neopentoyl, pivaloyl,and the like. A wide variety of activating groups for forming the acylderivative may be used to prepare the required acylating agent,including but not limited to anhydrides, chlorides, triflates, bromides,and the like. In one aspect, the sterically hindered acylating agent isbenzoic anhydride, or an equivalent activated benzoyl reagent capable offorming a benzoyl ester at the 2′ or both the 2′ and 4′ positions. Inanother embodiment R¹⁰⁰ is an optionally substituted benzoyl group, andthe process includes an optionally substituted benzoic anhydride, or anequivalent activated optionally substituted benzoylating reagent capableof forming the optionally substituted benzoyl ester.

Acylation is generally performed in the presence of a solvent and abase. Illustrative solvents include, but are not limited to, ethylacetate, dichloromethane, acetone, pyridine and the like, and mixturesthereof. Illustrative bases include but are not limited to inorganicbases, such as sodium and potassium bicarbonates and carbonates, sodiumand potassium hydroxides, and the like, and mixtures thereof; and aminebases, such as pyridine, dimethylaminopyridine (DMAP), triethylamine(TEA), diisopropylethylamine (DIPEA, Hünigs base),1,4-diazabicyclo[2.2.2]octane (DABCO), and the like, and mixturesthereof. The reaction may be performed at a variety of temperatures,such as in the range from about 0° C. to about 60° C., andillustratively at about 10° C. to about 30° C.

In another illustrative embodiment, processes are described forpreparing compounds of formulae

and salts thereof. The processes are generally performed in the presenceof a polar solvent, including polar protic and polar aprotic solvents,or a mixture thereof. Illustrative polar protic solvents include, butare not limited to water, alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol, iso-butyl alcohol, tert-butylalcohol, methoxyethanol, ethoxyethanol, pentanol, neo-pentyl alcohol,tert-pentyl alcohol, cyclohexanol, ethylene glycol, propylene glycol,benzyl alcohol, formamide, N-methylacetamide, N-methylformamide,glycerol, and the like, and mixtures thereof. Illustrative polar aproticsolvents include, but are not limited to dimethylformamide (DMF),dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),acetonitrile, dimethylsulfoxide (DMSO), propionitrile, ethyl formate,methyl acetate, hexachloroacetone, HMPA, HMPT, acetone, ethyl methylketone, ethyl acetate, isopropyl acetate, t-butyl acetate, sulfolane,N,N-dimethylpropionamide, nitromethane, nitrobenzene, tetrahydrofuran(THF), methyl tetrahydrofuran, dioxane, polyethers, and the like, andmixtures thereof. The processes may also be performed in the presence ofan additional base. Illustrative bases include, but are not limited toDBU, DABCO, TEA, DIPEA, piperidine, and the like, and mixtures thereof.

In another illustrative embodiment, processes are described forpreparing compounds of formulae

and salts thereof. The processes are generally performed in the presenceof an acid. Illustrative acids include, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid, trifluoroacetic acid, formic acid,hydrofluoric acid, and the like, and mixtures thereof. In one variation,the acid is hydrochloric acid. The processes are generally performed ina solvent such as water, a polar organic solvent, including alcoholssuch as methanol, ethanol, isopropanol, n-propanol, tert-butanol,n-butanol, and the like, and mixtures thereof. The processes may beperformed at a wide variety of temperatures, including temperatures inthe range from about 0° C. to about 70° C., and illustratively in therange from about 20° C. to about 60° C.

In another illustrative embodiment, processes are for preparingcompounds of formula

and salts thereof. The processes are generally performed in the presenceof an oxidizing agent. Illustrative oxidizing reagents and conditions,include but are not limited to Corey-Kim oxidation, such asdimethylsulfide/N-chlorosuccinimide (DMS/NCS),di-n-butylsulfide/N-chlorosuccinimide, Dess-Martin reagent,Pfitzner-Moffat methods and modifications thereof, Swern conditions,such as DMSO/oxalyl chloride, DMSO/phosphorous pentoxide, DMSO/p-toluenesulfonyl chloride, DMSO/acetic anhydride, DMSO/trifluoroaceticanhydride, and DMSO/thionyl chloride, manganese, chromium and seleniumreagents, tertiary amine oxides, Ni(Ac)₂/hypochlorite,DMSO/EDAC.HCl/pyridine.TFA and the like, and variations thereof, such asby including one or more phase-transfer catalysts.

In another illustrative embodiment, process are described for preparingcompounds of formulae

and salts thereof. The processes are generally performed in the presenceof a fluorinating agent. Illustrative fluorinating agents include(PhSO₂)₂N—F (NFSI or N-fluorosulfonimide), F-TEDA, F-TEDA-BF₄,1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate), and the like, in the presence of solvent andbase, such as t-BuOK.

In another illustrative embodiment, processes are described forpreparing compounds of formulae

and salts thereof via Huisgen cyclization in the presence of a coppercatalyst and base. The Huisgen cyclization is generally performed eithersolvent-free, in water or in an organic solvent such as acetonitrile ortoluene, in the presence of base. Illustrative bases include but are notlimited to organic bases, including alkyl and heteroaryl bases, such astriethylamine, diisopropylethylamine, DABCO, pyridine, lutidine, and thelike, and inorganic bases, such as NaOH, KOH, K₂CO₃, NaHCO₃, and thelike. The base is illustratively diisopropyl ethyl amine (DIPEA). Thereaction is carried out at temperatures ranging from 20° C. to 80° C.The reaction may also be promoted with the use of a catalyst, includingbut not limited to a copper halide, illustratively copper iodide. Theratio of CuI to azide is illustratively from about 0.01 to 1 to about0.1 to 1. In an alternate embodiment, the catalyst is an organiccatalyst, such as phenolphthalein. Additional reaction conditions aredescribed by Sharpless et al. in U.S. Patent Application Publication No.US 2005/0222427, Liang et al. in Bioorg. Med. Chem. Lett. 15 (2005)1307-1310, and Romero et al. in Tetrahedron Letters 46 (2005) 1483-1487,the disclosures of which are incorporated herein by reference.

In another illustrative embodiment, processes are described fordeprotecting compounds of formula

and salts thereof with an alcohol to prepare the correspondingdeprotected compound of formula (I). Illustrative alcohols include, butare not limited to, methanol, ethanol, n-propanol, isopropanol,tert-butanol, n-butanol or mixtures thereof. Illustratively, the alcoholis methanol. The reaction may be performed at a temperature of about 0°C. to about 100° C., or at about 20° C. to about 70° C. The reaction mayalso be performed in the presence of mineral acid, such as a mineralacid selected from HCl, H₂SO₄ and the like, and mixtures thereof. In oneillustrative embodiment the reaction is carried out in methanol at atemperature of about 55° C.

In another illustrative embodiment, processes are described for reducingcompounds of formula

and salts thereof. The processes are generally performed in the presenceof a reducing agent. Illustrative reducing agents include, but are notlimited to, hydrogen gas, iron and an acid, transfer hydrogenationagents, Raney-Ni, nickel sponge, metal catalysts, such as Pt, Pd, andthe like.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof. In another embodiment, N^(P) is an amide, orcarbamate, such as Bz-NH, CF₃C(O)—NH, Cbz-NH, Boc-NY, Fmoc-NY, BsMoc-NH,Trityl-NH, MeOTrityl ((4-methoxyphenyl)diphenylmethyl)-NH, and the like.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

In another illustrative embodiment, described herein are compounds offormulae

and salts thereof.

It is to be understood that in each of the foregoing embodiments, ineach instance, the selection of each of R¹⁰⁰, N^(P), A, B, C, C^(P), W,and L is independently made from any of the species, subgenera, andgenera described herein. In addition, it is to be understood that everycombination of each of those selections of R¹⁰⁰, N^(P), A, B, C, C^(P),W, and L is described herein, including any combinations of speciesthereof, subgenera thereof, and genera thereof.

In each of the foregoing and each of the following embodiments, it isalso to be understood that the formulae include and represent any andall crystalline forms, partially crystalline forms, and non-crystallineand/or amorphous forms of the compounds.

In each of the foregoing and each of the following embodiments, it isalso to be understood that the formulae include and represent not onlyall pharmaceutically acceptable salts of the compounds, but also includeany and all hydrates and/or solvates of the compound formulae. It isappreciated that certain functional groups, such as the hydroxy, amino,and like groups form complexes and/or coordination compounds with waterand/or various solvents, in the various physical forms of the compounds.Accordingly, the above formulae are to be understood to be a descriptionof such hydrates and/or solvates, including pharmaceutically acceptablesolvates.

As used herein, the term “solvates” refers to compounds described hereincomplexed with a solvent molecule. It is appreciated that compoundsdescribed herein may form such complexes with solvents by simply mixingthe compounds with a solvent, or dissolving the compounds in a solvent.It is appreciated that where the compounds are to be used aspharmaceuticals, such solvents are pharmaceutically acceptable solvents.It is further appreciated that where the compounds are to be used aspharmaceuticals, the relative amount of solvent that forms the solvateshould be less than established guidelines for such pharmaceutical uses,such as less than International Conference on Harmonization (ICH)Guidelines. It is to be understood that the solvates may be isolatedfrom excess solvent by evaporation, precipitation, and/orcrystallization. In some embodiments, the solvates are amorphous, and inother embodiments, the solvates are crystalline.

As used herein, the term “alkyl” includes a chain of carbon atoms, whichis optionally branched. As used herein, the terms “alkenyl” and“alkynyl” each include a chain of carbon atoms, which is optionallybranched, and include at least one double bond or triple bond,respectively. It is to be understood that alkynyl may also include oneor more double bonds. It is to be further understood that in certainembodiments, alkyl is advantageously of limited length, includingC₁-C₂₄, C₁-C₁₂, C₁-C₈, C₁-C₆, and C₁-C₄, and C₂-C₂₄, C₂-C₁₂, C₂-C₈,C₂-C₆, and C₂-C₄, and the like Illustratively, such particularly limitedlength alkyl groups, including C₁-C₈, C₁-C₆, and C₁-C₄, and C₂-C₈,C₂-C₆, and C₂-C₄, and the like may be referred to as lower alkyl. It isto be further understood that in certain embodiments alkenyl and/oralkynyl may each be advantageously of limited length, including C₂-C₂₄,C₂-C₁₂, C₇-C₈, C₂-C₆, and C₂-C₄, and C₃-C₂₄, C₃-C₁₂, C₃-C₈, C₃-C₆, andC₃-C₄, and the like Illustratively, such particularly limited lengthalkenyl and/or alkynyl groups, including C₂-C₈, C₂-C₆, and C₂-C₄, andC₃-C₈, C₃-C₆, and C₃-C₄, and the like may be referred to as loweralkenyl and/or alkynyl. It is appreciated herein that shorter alkyl,alkenyl, and/or alkynyl groups may add less lipophilicity to thecompound and accordingly will have different pharmacokinetic behavior.In embodiments of the invention described herein, it is to beunderstood, in each case, that the recitation of alkyl refers to alkylas defined herein, and optionally lower alkyl. In embodiments of theinvention described herein, it is to be understood, in each case, thatthe recitation of alkenyl refers to alkenyl as defined herein, andoptionally lower alkenyl. In embodiments of the invention describedherein, it is to be understood, in each case, that the recitation ofalkynyl refers to alkynyl as defined herein, and optionally loweralkynyl. Illustrative alkyl, alkenyl, and alkynyl groups are, but notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl,heptyl, octyl, and the like, and the corresponding groups containing oneor more double and/or triple bonds, or a combination thereof.

As used herein, the term “alkylene” includes a divalent chain of carbonatoms, which is optionally branched. As used herein, the term“alkenylene” and “alkynylene” includes a divalent chain of carbon atoms,which is optionally branched, and includes at least one double bond ortriple bond, respectively. It is to be understood that alkynylene mayalso include one or more double bonds. It is to be further understoodthat in certain embodiments, alkylene is advantageously of limitedlength, including C₁-C₂₄, C₁-C₁₂, C₁-C₈, C₁-C₆, and C₁-C₄, and C₂-C₂₄,C₂-C₁₂, C₂-C₈, C₂-C₆, and C₂-C₄, and the like. Illustratively, suchparticularly limited length alkylene groups, including C₁-C₈, C₁-C₆, andC₁-C₄, and C₂-C₈, C₂-C₆, and C₂-C₄, and the like may be referred to aslower alkylene. It is to be further understood that in certainembodiments alkenylene and/or alkynylene may each be advantageously oflimited length, including C₂-C₂₄, C₂-C₁₂, C₂-C₈, C₂-C₆, and C₂-C₄, andC₃-C₂₄, C₃-C₁₂, C₃-C₈, C₃-C₆, and C₃-C₄, and the like. Illustratively,such particularly limited length alkenylene and/or alkynylene groups,including C₂—C, C₂-C₆, and C₂-C₄, and C₃-C₈, C₃-C₆, and C₃-C₄, and thelike may be referred to as lower alkenylene and/or alkynylene. It isappreciated herein that shorter alkylene, alkenylene, and/or alkynylenegroups may add less lipophilicity to the compound and accordingly willhave different pharmacokinetic behavior. In embodiments of the inventiondescribed herein, it is to be understood, in each case, that therecitation of alkylene, alkenylene, and alkynylene refers to alkylene,alkenylene, and alkynylene as defined herein, and optionally loweralkylene, alkenylene, and alkynylene. Illustrative alkyl groups are, butnot limited to, methylene, ethylene, n-propylene, isopropylene,n-butylene, is obutylene, sec-butylene, pentylene, 1,2-pentylene,1,3-pentylene, hexylene, heptylene, octylene, and the like.

As used herein, the term “cycloalkyl” includes a chain of carbon atoms,which is optionally branched, where at least a portion of the chain incyclic. It is to be understood that cycloalkylalkyl is a subset ofcycloalkyl. It is to be understood that cycloalkyl may be polycyclic.Illustrative cycloalkyl include, but are not limited to, cyclopropyl,cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl,adamantyl, and the like. As used herein, the term “cycloalkenyl”includes a chain of carbon atoms, which is optionally branched, andincludes at least one double bond, where at least a portion of the chainin cyclic. It is to be understood that the one or more double bonds maybe in the cyclic portion of cycloalkenyl and/or the non-cyclic portionof cycloalkenyl. It is to be understood that cycloalkenylalkyl andcycloalkylalkenyl are each subsets of cycloalkenyl. It is to beunderstood that cycloalkyl may be polycyclic. Illustrative cycloalkenylinclude, but are not limited to, cyclopentenyl, cyclohexylethen-2-yl,cycloheptenylpropenyl, and the like. It is to be further understood thatchain forming cycloalkyl and/or cycloalkenyl is advantageously oflimited length, including C₃-C₂₄, C₃-C₁₂, C₃-C₈, C₃-C₆, and C₅-C₆. It isappreciated herein that shorter alkyl and/or alkenyl chains formingcycloalkyl and/or cycloalkenyl, respectively, may add less lipophilicityto the compound and accordingly will have different pharmacokineticbehavior.

As used herein, the term “heteroalkyl” includes a chain of atoms thatincludes both carbon and at least one heteroatom, and is optionallybranched. Illustrative heteroatoms include nitrogen, oxygen, and sulfur.In certain variations, illustrative heteroatoms also include phosphorus,and selenium. As used herein, the term “cycloheteroalkyl” includingheterocyclyl and heterocycle, includes a chain of atoms that includesboth carbon and at least one heteroatom, such as heteroalkyl, and isoptionally branched, where at least a portion of the chain is cyclic.Illustrative heteroatoms include nitrogen, oxygen, and sulfur. Incertain variations, illustrative heteroatoms also include phosphorus,and selenium. Illustrative cycloheteroalkyl include, but are not limitedto, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl,morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

As used herein, the term “aryl” includes monocyclic and polycyclicaromatic carbocyclic groups, each of which may be optionallysubstituted. Illustrative aromatic carbocyclic groups described hereininclude, but are not limited to, phenyl, naphthyl, and the like. As usedherein, the term “heteroaryl” includes aromatic heterocyclic groups,each of which may be optionally substituted. Illustrative aromaticheterocyclic groups include, but are not limited to, pyridinyl,pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl,quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl,benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl,benzisothiazolyl, and the like.

As used herein, the term “amino” includes the group NH₂, alkylamino, anddialkylamino, where the two alkyl groups in dialkylamino may be the sameor different, i.e. alkylalkylamino. Illustratively, amino includesmethylamino, ethylamino, dimethylamino, methylethylamino, and the like.In addition, it is to be understood that when amino modifies or ismodified by another term, such as aminoalkyl, or acylamino, the abovevariations of the term amino are included therein. Illustratively,aminoalkyl includes methylaminoalkyl, ethylaminoalkyl,dimethylaminoalkyl, methylethylaminoalkyl, and the like. Illustratively,acylamino includes acylmethylamino, acylethylamino, and the like.

As used herein, the term “amino and derivatives thereof” includes aminoas described herein, and alkylamino, alkenylamino, alkynylamino,heteroalkylamino, heteroalkenylamino, heteroalkynylamino,cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino,cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamino,arylalkynylamino, heteroarylamino, heteroarylalkylamino,heteroarylalkenylamino, heteroarylalkynylamino, acylamino, and the like,each of which is optionally substituted. The term “amino derivative”also includes urea, carbamate, and the like.

As used herein, the term “hydroxy and derivatives thereof” includes OH,and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy,heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy,cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy,arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy, heteroarylalkenyloxy,heteroarylalkynyloxy, acyloxy, and the like, each of which is optionallysubstituted. The term “hydroxy derivative” also includes carbamate, andthe like.

As used herein, the term “thio and derivatives thereof” includes SH, andalkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio,heteroalkynylthio, cycloalkylthio, cycloalkenylthio,cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio,arylalkenylthio, arylalkynylthio, heteroarylthio, heteroarylalkylthio,heteroarylalkenylthio, heteroarylalkynylthio, acylthio, and the like,each of which is optionally substituted. The term “thio derivative” alsoincludes thiocarbamate, and the like.

As used herein, the term “acyl” includes formyl, and alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, heteroalkylcarbonyl,heteroalkenylcarbonyl, heteroalkynylcarbonyl, cycloalkylcarbonyl,cycloalkenylcarbonyl, cycloheteroalkylcarbonyl,cycloheteroalkenylcarbonyl, arylcarbonyl, arylalkylcarbonyl,arylalkenylcarbonyl, arylalkynylcarbonyl, heteroarylcarbonyl,heteroarylalkylcarbonyl, heteroarylalkenylcarbonyl,heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which isoptionally substituted.

As used herein, the term “carbonyl and derivatives thereof” includes thegroup C(O), C(S), C(NH) and substituted amino derivatives thereof.

As used herein, the term “carboxylic acid and derivatives thereof”includes the group CO₂H and salts thereof, and esters and amidesthereof, and CN.

As used herein, the term “sulfinic acid or a derivative thereof”includes SO₂H and salts thereof, and esters and amides thereof.

As used herein, the term “sulfonic acid or a derivative thereof”includes SO₃H and salts thereof, and esters and amides thereof.

As used herein, the term “sulfonyl” includes alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, heteroalkylsulfonyl,heteroalkenylsulfonyl, heteroalkynylsulfonyl, cycloalkylsulfonyl,cycloalkenylsulfonyl, cycloheteroalkylsulfonyl,cycloheteroalkenylsulfonyl, arylsulfonyl, arylalkylsulfonyl,arylalkenylsulfonyl, arylalkynylsulfonyl, heteroarylsulfonyl,heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl,heteroarylalkynylsulfonyl, acylsulfonyl, and the like, each of which isoptionally substituted.

The term “optionally substituted” as used herein includes thereplacement of hydrogen atoms with other functional groups on theradical that is optionally substituted. Such other functional groupsillustratively include, but are not limited to, amino, hydroxyl, halo,thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl,heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonicacids and derivatives thereof, carboxylic acids and derivatives thereof,and the like. Illustratively, any of amino, hydroxyl, thiol, alkyl,haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid isoptionally substituted.

As used herein, the terms “optionally substituted aryl” and “optionallysubstituted heteroaryl” include the replacement of hydrogen atoms withother functional groups on the aryl or heteroaryl that is optionallysubstituted. Such other functional groups illustratively include, butare not limited to, amino, hydroxy, halo, thio, alkyl, haloalkyl,heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids andderivatives thereof, carboxylic acids and derivatives thereof, and thelike. Illustratively, any of amino, hydroxy, thio, alkyl, haloalkyl,heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl,heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid isoptionally substituted.

Illustrative substituents include, but are not limited to, a radical—(CH₂)_(x)Z^(x), where x is an integer from 0-6 and Z^(X) is selectedfrom halogen, hydroxy, alkanoyloxy, including C₁-C₆ alkanoyloxy,optionally substituted aroyloxy, alkyl, including C₁-C₆ alkyl, alkoxy,including C₁-C₆ alkoxy, cycloalkyl, including C₃-C₈ cycloalkyl,cycloalkoxy, including C₃-C₈ cycloalkoxy, alkenyl, including C₂-C₆alkenyl, alkynyl, including C₂-C₆ alkynyl, haloalkyl, including C₁-C₆haloalkyl, haloalkoxy, including C₁-C₆ haloalkoxy, halocycloalkyl,including C₃-C₈ halocycloalkyl, halocycloalkoxy, including C₃-C₈halocycloalkoxy, amino, C₁-C₆ alkylamino, (C₁-C₆ alkyl)(C₁-C₆alkyl)amino, alkylcarbonylamino, N—(C₁-C₆ alkyl)alkylcarbonylamino,aminoalkyl, C₁-C₆ alkylaminoalkyl, (C₁-C₆ alkyl)(C₁-C₆ alkyl)aminoalkyl,alkylcarbonylaminoalkyl, N—(C₁-C₆ alkyl)alkylcarbonylaminoalkyl, cyano,and nitro; or Z^(x) is selected from —CO₂R⁴ and —CONR⁵R⁶, where R⁴, R⁵,and R⁶ are each independently selected in each occurrence from hydrogen,C₁-C₆ alkyl, aryl-C₁-C₆ alkyl, and heteroaryl-C₁-C₆ alkyl.

Illustrative heterocycles include, but are not limited to pyrrolidines,piperidines, oxazolidines, isoxazolidines, thiazolidines,isothiazolidines, pyrrolidinones, piperidinones, oxazolidinones,isoxazolidinones, thiazolidinones, isothiazolidinones, and succinimides.

As used herein, the term “leaving group” refers to a reactive functionalgroup that generates an electrophilic site on the atom to which it isattached such that nucleophiles may be added to the electrophilic siteon the atom. Illustrative leaving groups include, but are not limitedto, halogens, optionally substituted phenols, acyloxy groups, sulfonoxygroups, and the like. It is to be understood that such leaving groupsmay be on alkyl, acyl, and the like. Such leaving groups may also bereferred to herein as activating groups, such as when the leaving groupis present on acyl. In addition, conventional peptide, amide, and estercoupling agents, such as but not limited to PyBop, BOP—Cl, BOP,pentafluorophenol, isobutylchloroformate, and the like, form variousintermediates that include a leaving group, as defined herein, on acarbonyl group.

It is to be understood that where members are grouped together in acommon manner, such as in a Markush group, the present inventionencompasses not only the entire group listed as a whole, but each memberof the group individually and all possible subgroups of the main group.Accordingly, for all purposes, the present invention encompasses notonly the main group, but also the main group absent one or more of thegroup members. The present invention also envisages the explicitexclusion of one or more of any of the group members in the claimedinvention.

In another embodiment, the following process steps and compounds areeach individually described herein.

The corresponding process where C is replace by C^(P) in one or moresteps is also described herein.

In another embodiment, the following process steps and compounds areeach individually described herein.

where RC is amino, or a protected amino derivative such as N^(P), ornitro. The corresponding process where RC is N^(P) is also describedherein.

In another embodiment, the following process steps and compounds areeach individually described herein.

In another embodiment, the following process steps and compounds areeach individually described herein.

The processes and compounds described herein are further illustrated bythe following examples. The following examples are intended to beillustrative and should not be construed or considered to be limiting inany manner.

EXAMPLES Example. CEM-101 is Prepared According to the Following Process

Example. Compounds of the Formula

where OM is a hydroxy protecting group, such as an acyl group, includingacetyl, benzoyl, and the like, are prepared using conventionalprocesses, such as but not limited to processes described in PCTInternational Publication Nos. WO/2009/055557 and WO/2011/146829, thedisclosures of which are incorporated herein by reference, in theirentirety.

Example. Stage 1

Preparation of 2′,4″-di-O-benzoyl-6-O-methylerythromycin A. 125 mL ofethyl acetate was added to 25 g clarithromycin A. 26.5 g benzoicanhydride, 5.7 g 4-dimethylamino pyridine and 6.7 g triethylamine wereadded to the reaction mixture at 25° C. to 35° C. The reaction mixturewas stirred for about 70 hours at ambient temperature. After completionof the reaction, ethyl acetate was distilled out to obtain the titlecompound.

Example. Stage 2

Preparation of10,11-anhydro-2′,4″-di-O-benzoyl-12-O-imidazolylcarbonyl-6-O-methylerythromycinA. Dimethylformamide (DMF, 100 mL) was added to2′,4″-di-O-benzoyl-6-O-methylerythromycin A at 25-35° C., then1,8-diazabicyclo[5.4.0]undec-7-ene (DBU 6.4 g) was added to the reactionmixture and stirred at ambient temperature. 1,1′-Carbonyldiimidazole(CDI, 17 g) was added to the reaction and it was stirred untilcompletion at ambient temperature. The title compound is isolated byaddition of water, and collecting the resulting precipitate.

Example. Compounds of Formulae (A)

where A, B, C, and C^(P) are as defined herein in each of theembodiments described herein, are prepared using conventional processes.Similarly, compounds of formula (A1)

are prepared using conventional processes. Similarly, compounds offormula (A2)

where N^(P) is as defined herein in each of the embodiments describedherein, are prepared using conventional processes. It is appreciatedthat the aminophenyl group of the compounds of formula (A2) may beprotected prior to addition to Intermediate 3. Amino protected amide,carbamate, and urea derivatives are also prepared using conventionalprocesses.

Example. Illustratively, the Foregoing Compounds May be Prepared by theFollowing Processes, Illustrated for Compounds of Formula (A1)

It is to be understood that the foregoing process may be used to preparecompounds of the formula (A) and/or (A1), including amino-protectedderivatives thereof by the appropriate selection of starting materials,such as

and the like, where A, B, C, C″, and N″ are as defined herein in each ofthe embodiments described herein.

Example. Stage 3

To a solution Stage-2 compound dissolved in 3000 mL of DMF (5.0 v,M/C<1.0%) at 0-5° C. was added drop wise DBU followed by side chain inportions. The reaction mixture was allowed to come to room temperatureand stirred for 36 h. The HPLC recorded after 36 h showed <1% ofun-reacted Stage-2 compound.

The reaction mixture was poured into ice cold water (6000 mL) andstirred for 2 h. The solid was filtered, washed with water (2500 mL) andsuck dried for 2 h to obtain 650 g of crude product with 85% HPLCpurity.

The crude product was added at room temperature to a bi-phasic solutionof ethyl acetate (1500 mL) and 1 N aqueous HCl (1500 mL) and stirred for1 h. The solid was filtered, washed with ethyl acetate (600 mL) and suckdried for 2 h. The solid was suspended again in ethyl acetate (1500 mL),stirred for 1 h at room temperature and filtered. The filter cake wasdried in a vacuum oven at 40-45° C. till the moisture content was notmore than 3%. The pure product was obtained as a white solid in 88%yield (620 g) and 98% purity.

Example. Stage 4

To a solution of Stage-3 compound in 1800 mL of acetone at 0 to 5° C.was added 272 mL of methanolic HCl slowly and the reaction mixture wasstirred for additional 30 min at the same temperature. The reaction wasthen allowed to come to room temperature and stirred for 16 h.

After completion of the reaction, the reaction mixture was distilledunder reduced pressure and obtained the product as a gummy residue. Thecrude mass was stirred with ethyl acetate and decanted to remove benzoylcladinose and other impurities. Alternately, the gummy residue wasdissolved in water and then extracted with toluene to remove benzoylcladinose and other impurities. Then the aqueous layer was basifiedusing 10% aqueous sodium hydroxide solution, then extracted with ethylacetate to get decladinose product. Optionally, the distillation wasperformed after adjusting the pH with aqueous sodium bicarbonatesolution.

The suspension was filtered and washed with acetone (200 mL). The pH ofthe filtrate was adjusted to 5 using saturated aqueous sodiumbicarbonate solution and the solvents acetone and methanol weredistilled under reduced pressure (below 40-45° C.). The residue wasextracted with dichloromethane (3×200 mL) and the combined organic layerwas dried over anhydrous sodium sulphate and distilled dichloromethaneto obtain 130 g of crude product. The HPLC showed benzoyl cladinose andthe desired product as major peaks (together showed 98% by area).

The crude product was stirred at room temperature in 5% ethyl acetate inhexanes (40 mL of ethyl acetate and 760 mL of hexanes) for 2 h andfiltered. The filter cake was washed with 5% ethyl acetate in hexanes(10 mL of ethyl acetate and 190 mL of hexanes) and dried in a vacuumoven at 40-45° C. till the LOD was note more than 1% and M/C not morethan 0.5%. The pure was obtained as a white solid in 86.6% yield (132 g)and 92.0% HPLC purity.

Example. Stage 5

To a solution of N-chlorosuccinimide dissolved in 1600 mL ofdichloromethane at −50° C. was added dimethyl sulfide over a period of30 min, maintaining the temperature between −40 to −35° C. Afterstirring the reaction mixture for 60 min, a solution of Stage-4 compoundin 1400 mL of dichloromethane was added over a period of 2 h maintainingthe internal temperature between −40 to −35° C. The reaction mixture wasstirred for further 90 min at −45° C. (HPLC showed <1% of the un-reactedstarting material) and 177 mL of N-diisopropylethylamine was addedcautiously over a period of 1 h maintaining the internal temperaturebetween −45 to −40° C. The reaction mixture was warmed to 10° C. andstirred for 90 min.

To the reaction mixture 3000 mL of water was added and warmed thereaction mass to room temperature (25-30° C.). The organic layer wasseparated and washed successively with 1N aqueous HCl (2000 mL), water(2000 mL) followed by 10% aqueous sodium bi-carbonate solution (2000mL). The organic layer was then dried over anhydrous sodium sulphate andthe solvent was distilled under reduced pressure to obtain 190 g ofcrude product having 85% HPLC purity.

The crude product was suspended in 400 mL of MTBE and heated at 55° C.for 2 h. The suspension was cooled to room temperature and stirred for 1h. The solid was filtered and dried in a vacuum oven at 40-45° C. toobtain the pure product with LOD not more than 1.0% and M/C not morethan 0.5%. The pure was obtained as a white solid in 89.1% yield (178 g)and 93.0% HPLC purity.

Example. Stage 6

To a solution of Stage-5 compound dissolved in 9:1 mixture of DMF:THF(1350 mL of DMF and 150 mL of THF) at −65 to −60° C. was added K^(t)OBuin 10 equal portions and stirred the reaction mixture for 60 min at thesame temperature. A solution of NFSI dissolved in 9:1 mixture of DMF:THF(900 mL of DMF and 100 mL of THF) was added to the reaction mixture overa period of 3-4 h maintaining the internal temperature between −65 to−60° C. The contents were stirred for further 60 min at the sametemperature.

The reaction mixture was poured into 1000 mL of saturated aqueous NaHCO₃solution maintained at 0° C. and stirred for 30 min. The precipitatedsolid was filtered, washed with 2×100 mL of water and dried in a vacuumoven at 45-50° C. till LOD was not more than 3.0% and M/C not more than3%. The crude product was obtained a brown solid in 87.6% yield (90 g)and 80-90% HPLC purity. Further purification may be performed usingcolumn chromatography on fluorisil

Example. Stage 7

A solution of Stage-6 compound dissolved in 765 mL of methanol washeated at reflux temperature for 12 h. The HPLC after 12 h showed <1% ofthe starting material and at this stage charcoal was added and stirredfor further 2 h at reflux temperature.

The suspension was filtered over a celite bed and the filtrate wasconcentrated under reduced pressure (at <45° C.) to obtain the crudeproduct as brown gummy solid.

The crude product was stirred at room temperature in 5% MTBE in hexanes(14 mL of MTBE and 255 mL of hexanes) for 2 h. The solid was filteredand the purification was repeated two more times with 5% MTBE in hexanes(14 mL of MTBE and 255 mL of hexanes each time) to obtain 73 g ofproduct (90% yield) as pale brown solid with 90.54% purity.

Example. Stage 8

To a solution of Stage-7 compound dissolved in 450 mL of methanol wasadded 1.0 equiv of acetic acid followed by 3.3 w/w % of Pd—C. Thesuspension was stirred at 40° C. under 40 psi of hydrogen pressure for 6h and HPLC showed 15% conversion of the starting material. The secondlot of 6.6% w/w of Pd—C was added and continued to stir the reaction at40° C. under 40 psi of hydrogen pressure for 24 h. At this stage HPLCshowed 55% conversion of the starting material. The third lot of 3.3%Pd—C was added to the reaction mixture and after 12 h<1% of un-reactedstarting material was observed.

The reaction mixture was cooled to room temperature and the suspensionwas filtered through a celite bed. The filter cake was washed with 200mL of methanol and the combined filtrates were subjected to distillationunder reduced pressure (below 45° C. temperature) to obtain gummy solid.The gummy solid was dissolved in 125 mL of dichloromethane and washedwith 25 mL of aqueous ammonia solution. The organic layer was dried oversodium sulphate and dichloromethane was distilled to obtain crudeproduct as pale brown solid (21 g) in 80% HPLC purity.

The crude product was suspended in 50 mL of IPA and stirred at 55-60° C.for 3 days. The suspension was allowed to cool to room temperature andfiltered. The filter cake was washed with 25 mL of cold IPA and driedunder vacuum at 40-45° C. to obtain 12.6 g (52% yield) of the productwith 94% purity.

Example. CEM-101 is Prepared According to the Following Process

Example. Intermediate 4

Intermediate 4 is prepared as described in PCT International PublicationNos. WO/2009/055557 and WO/2011/146829 from clarithromycin, andgenerally according to the process shown in Scheme 1. 62 g ofIntermediate 1 was prepared in 80% yield from clarithromycin. 15 g ofIntermediate 2 was prepared from Intermediate 1 in 93% yield.Cyclization of Intermediate 2 gave 6.6 g of intermediate 3 in 86% yield.Removal of cladinose from intermediate 3 Step 4 gave 4.4 g ofIntermediate 4 in 85% yield. The product identity was confirmed by massspectrometry and NMR.

Example. Intermediate 5

Trifluoroacetic anhydride (113 mg, 0.54 mmol) was added dropwise to asolution of Intermediate 4 (500 mg, 0.54 mmol) in anhydrous DCM (9 mL)at 0° C. After the addition, the reaction mixture was stirred at 0° C.for 1 h. The reaction mixture was diluted with DCM, washed successivelywith dilute aqueous NaHCO₃ solution and brine, and dried over anhydrousMgSO₄. After filtration, the filtrate was concentrated to dryness togive 450 mg of crude Intermediate 5 as a light brown solid. Massspectroscopy analysis of crude Intermediate 5 showed the desired productpeak as the major component. The ¹H-NMR spectrum of crude Intermediate 5showed peaks corresponding to the desired structure of the product. The¹H-NMR spectrum also showed the presence of unreacted Intermediate 4.The material (˜85% purity) was used without further purification.

Example. Intermediate 6

To a solution of Intermediate 5 (100 mg, 0.097 mmol, ˜85% purity) inanhydrous DCM (3 mL) was added Dess-Martin periodinane (50 mg, 0.116mmol, 1.2 eq). The resulting reaction mixture was stirred at roomtemperature for 1.5 h. The reaction mixture was diluted with DCM, washedsuccessively with dilute aqueous sodium thiosulfate solution and brine,and dried over anhyd MgSO₄. After filtration, the filtrate concentratedto dryness. The crude product was subjected to silica gel columnchromatography (eluent: acetone/DCM, 20/80, v/v) to afford 55 mg of pureIntermediate 6 as a white solid in 72% yield. The ¹H-NMR spectrum ofIntermediate 6 confirmed the structure of the product and its goodpurity.

Example. Intermediate 7

A solution of Intermediate 6 (82 mg, 0.08 mmol) in DMF (1 mL) was cooledto −30° C. DBU (14 mg, 0.088 mmol) was added, and the resulting mixturewas stirred at −30° C. for 20 min. To the reaction mixture stirring at−30° C. was added dropwise a solution of NSFI (25 mg, 0.08 mmol) in DMF(1 mL). After the addition, the reaction mixture was stirred at −30° C.for 20 min. The reaction mixture was quenched with dilute aqueoussolution of NaHCO₃ and extracted with DCM. The combined DCM extract waswashed with brine, and dried over anhyd MgSO₄. After filtration, thefiltrate was concentrated to dryness. The crude product was subjected tosilica gel column chromatography (eluent: acetone/DCM, 20/80, v/v) toafford 61 mg of pure Intermediate 7 as a white solid in 86% yield. The¹H-NMR spectrum of Intermediate 7 confirmed the desired structure of theproduct and its good purity.

Example. CEM-101

A solution of Intermediate 7 (60 mg) in methanol (1 mL) containing 0.3mL of NH₄OH was stirred at room temperature overnight. Mass spectroscopyanalysis of an aliquot of the reaction mixture showed a peak with a Mwcorresponding to CEM-101 as the major component along with unreactedIntermediate 7. The reaction mixture was diluted with DCM, washedsuccessively with water and brine, and dried over anhyd MgSO₄. Afterfiltration, the filtrate was concentrated to dryness. The crude productwas dissolved in methanol (10 mL) and heated at reflux for one hour. Thereaction mixture was concentrated to a small volume and the residue wassubjected to silica gel column chromatography (eluent: DCM/MeOH/NH₄OH,95/5/0.5, by volume) to afford 40 mg of CEM-101. The ¹H-NMR spectrumconfirmed the desired structure of the product.

Example. Synthesis of Intermediate 3a

A mixture of intermediate 2 (1.0 g), protected side chain-HCl salt (1.3eq.), DBU (2.5 eq.), and DMF was heated at 40-70° C. with stirring undernitrogen. Reaction progress was monitored by TLC, HPLC, and MS. Whencomplete, the mixture was partitioned between DCM and brine, washed withwater, dried over anhydrous MgSO₄, filtered and evaporated. The residuewas purified by HPLC to give >90% yield of the title compound. ¹H NMRspectra and mass spectra (MW 1292) were consistent with the titlecompound.

Example. Synthesis of Intermediate 3a

A solution of Intermediate 3 (650 mg, 0.544 mmol) in anhydrous DCM (10mL) was cooled to 5° C. with an ice-bath. To this was addedtrifluoroacetic anhydride (172 mg, 0.82 mmol, 1.5 equivalent), and theresulting reaction mixture was stirred for 10 min at 5° C., beforegradual warming to ambient temperature over 1.5 hr. The reaction wasquenched with ice cold diluted aqueous NaHCO₃ and extracted with DCM.The combined DCM extract was washed with brine and dried over anhydrousMgSO₄. The drying agent was removed by filtration, and the filtrate wasconcentrated to dryness. The crude product was purified through silicagel column chromatography (eluent: DCM/MeOH/NH₄OH=95/5/0.5, by volume)to give 540 mg of product in 77% yield. Both the ¹H-NMR spectrum andmass spectrum of the product showed peaks conforming to the desiredstructure of Intermediate 3a.

Example. Synthesis of Intermediate 5

To a solution of Intermediate 3a (150 mg, 0.116 mmol) in acetone (3 mL)was added DBU (35 mg, 0.233 mmol, 2.0 equivalent), followed by conc. HCl(300 μL). The resulting reaction mixture was stirred at room temperaturefor 5 hrs. Mass analysis of an aliquot of the reaction mixture showedcomplete reaction with clean reaction profile. The reaction mixture waspoured into a mixture of DCM and ice water. The mixture was made basicby the addition of dilute NH₄OH and extracted with DCM. The combined DCMextract was washed with brine, dried over anhydrous MgSO₄. The dryingagent was removed by filtration, and the filtrate was concentrated todryness. The crude product was purified through silica gel columnchromatography (eluent: DCM/MeOH/NH₄OH=95/5/0.5, by volume) to give 103mg of Intermediate 5 in 86% of yield. The ¹H-NMR spectrum and massspectrum of the product showed peaks corresponding to those expected forthe desired structure of intermediate 5 with good purity.

Example. Synthesis of Intermediate 6a

To a solution of Intermediate 6, (1.0 mmol) in methanol (10 mL) is addedammonium hydroxide solution (NH₄OH, 30 mmol). The resulting clearsolution is stirred at ambient temperature overnight to give a turbidreaction mixture. The reaction mixture is concentrated to dryness,dissolved in DCM, washed successively with diluted aqueous NaHCO₃solution and brine, and then dried over anhydrous. MgSO₄. Afterfiltration to remove the drying agent, the filtrate is concentrated todryness to afford 0.8 mmol of Intermediate 6a(90% yield). The 1H-NMRspectrum and mass spectrum are consistent with the title compound.

1.-25. (canceled)
 26. A composition comprising solithromycin that issubstantially free of:

wherein A-B is (CH₂)₄.
 27. A compound of the formula:

wherein: A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)₂NH, or C(O)NHS(O)₂;B is saturated C₀C₁₀; or B is unsaturated C₂C₁₀; or AB taken together isalkylene, alkenylene, cycloalkylene, or arylene; C is hydrogen, halogen,hydroxy, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, and alkyl,alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl,each of which is optionally substituted; and R¹⁰⁰ is hydrogen or ahydroxyl protecting group.
 28. The compound of claim 27 wherein C isaryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which isoptionally substituted.
 29. The compound of claim 27 wherein A is CH₂.30. The compound of claim 27 wherein B is (CH₂)_(n), and n is an integerfrom 2-6.
 31. The compound of claim 27 of the formula:


32. The compound of claim 27 of the formula:


33. The compound of claim 32 wherein R¹⁰⁰ is hydrogen.
 34. Anintermediate of the formulae:

wherein: A is CH₂, C(O), C(O)O, C(O)NH, S(O)₂, S(O)2NH, or C(O)NHS(O)₂;B is saturated C₀C₁₀; or B is unsaturated C₂C₁₀; or AB taken together isalkylene, alkenylene, cycloalkylene, or arylene; C is hydrogen, halogen,hydroxy, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, and alkyl,alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl,each of which is optionally substituted; or C is C^(P), where C^(P) is aprotected form of C; R¹⁰⁰ is hydrogen or a hydroxyl protecting group;and N^(P) is NH₂ or protected amino.
 35. The intermediate of claim 34wherein C is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each ofwhich is optionally substituted.
 36. The intermediate of claim 34wherein A is CH₂.
 37. The intermediate of claim 34 wherein B is(CH₂)_(n), and n is an integer from 2-6.
 38. The intermediate of claim34 wherein B is (CH₂)_(n), and n is 2, 3, or
 4. 39. The intermediate ofclaim 34 wherein R¹⁰⁰ is acyl.
 40. The intermediate of claim 34 of theformula:


41. The intermediate of claim 34 of the formula:


42. The intermediate of claim 34 of the formula:


43. The intermediate of claim 34 of the formula:


44. The intermediate of claim 34 of the formulae: